Brain injury induces the subsequent development of epilepsy by unknown mechanisms. The primary unmet need and most urgent issue to address in epilepsy research is characterization of the biological factors underlying this process, which has been termed epileptogenesis. This is the focus of the present application. We have preliminary data implicating injury-mediated upregulation of a transcriptional repressor, Repressor Element 1 silencing transcription factor (REST) as a significant contributor to epilepsy disease development. REST is induced transiently by epileptogenic injury, and represses the expression of key genes in hippocampal neurons, altering limbic synaptic and circuit function, which in turn contributes to epilepsy development. Blocking REST effects, either indirectly by targeting REST-mediated transcriptional repression, or directly by blunting REST upregulation, reverse the synaptic and circuit effects evident during epileptogenesis, and retards or stops the subsequent development of epilepsy. Based on this preliminary data, we have formulated a Central Hypothesis: Epileptogenesis is a consequence of REST-mediated epigenetic modification in expression of key genes regulating excitability of the hippocampal dentate gyrus. In the present proposal, this Central Hypothesis will be tested in a series of studies integrating state of the art dynamic imaging, patch clamp, gene targeting, and in vivo recording techniques. We propose to examine how a) selective deletion of REST in forebrain principal neurons; b) selective deletion of REST in neurons within the hippocampal dentate gyrus or area CA1; and c) selective, temporally regulated synaptic silencing of dentate granule neurons modifies or blocks epilepsy onset and hippocampal circuit perturbations, both of which develop following status epilepticus. Successful implementation of these experimental approaches should provide significant insight into the mechanisms underlying the injury/epilepsy link responsible for acquired epilepsies. Understanding the mechanisms contributing to epilepsy emergence will immediately suggest new therapies targeting epileptognesis, many of which could translate quickly to the clinic. PUBLIC HEALTH RELEVANCE: Despite the fact that epilepsy is one of the most common chronic neurologic disorders, we know very little about the mechanisms which link brain injury with the subsequent emergence of spontaneous seizures, the clinical hallmark of epilepsy. This proposal will examine these mechanisms, focusing on the role of a specific repressor of gene transcription, which may play a significant role in epilepsy development. Using advanced imaging, patch clamp recording, gene targeting, and in vivo techniques in animal models of epilepsy, we will determine the mechanisms linking brain injury to epilepsy, facilitating the development of better, more effective treatments for the disease process underlying epilepsy development.